Expression of Dkk 1 in Endometrial Endometrioid Carcinoma & Its Correlation with Wnt / β-catenin Signaling Pathway

Objective: Endometrial cancer is the most common form of cancer affecting female reproductive organs. Most common histologic type endometrioid carcinoma constitutes 75 to 80% of all cases. Studies on Dkk1 expression profiles and its inhibitory role in Wnt signaling pathway in genesis and development of endometrial carcinoma are very few. This study aims to investigate Dkk1 expression in endometrial carcinoma and its correlation with Wnt/β-catenin pathway. Methods: A total of 160 formalin fixed paraffin embedded samples including 50 cases each of endometrial atypical hyperplasia and endometrioid endometrial carcinoma along with 30 cases each of proliferative and secretory endometrium were included in this study. We investigated expression pattern of Dkk1, E-cadherin, β-catenin and c-myc in endometrial atypical hyperplasia and carcinoma as well as compared with that of proliferative and secretory endometrium. Immunohistochemistry and analysis were performed from July, 2018 to June, 2020. Results: We showed decreasing pattern of immunopositivity for Dkk1, E-cadherin and β-catenin from proliferative/secretory endometrium to endometrial atypical hyperplasia and endometrioid carcinoma. Increasing c-myc immunopositivity was noted from proliferative/secretory endometrium to endometrial atypical hyperplasia and endometrioid carcinoma. Moreover, decreasing Dkk1 immunopositivity was well correlated with both E-cadherin, β-catenin and c-myc immunopositivity. Conclusion: Decreasing Dkk1 positivity from benign endometrium to endometrioid carcinoma suggests a negative regulatory function of Dkk1 in endometrioid carcinoma. Dkk1 is downregulated in Wnt signaling pathway in endometrioid endometrial carcinoma. Thus, Dkk1 can show promise as a biomarker for screening endometrioid carcinoma. Future researches can study the reactivation of the Dkk1 gene that could be a valuable strategy for antagonizing Wnt signaling pathway. Keywords: Endometrioid carcinoma, Dkk1, Wnt/β-catenin pathway, β-catenin, E-cadheri

Tissue biomarkers in prognostication of serous ovarian cancer following neoadjuvant chemotherapy

Serous ovarian cancer (SOC) is a significant cause of morbidity and mortality in females with poor prognosis because of advanced stage at presentation. Recently, neoadjuvant chemotherapy (NACT) is being used for management of advanced SOC, but role of tissue biomarkers in prognostication following NACT is not well established. The study was conducted on advanced stage SOC patients (n = 100) that were treated either conventionally (n = 50) or with NACT (n = 50), followed by surgery. In order to evaluate the expression of tissue biomarkers (p53, MIB1, estrogen and progesterone receptors, Her-2/neu, E-cadherin, and Bcl2), immunohistochemistry and semiquantitative scoring were done following morphological examination. Following NACT, significant differences in tumor histomorphology were observed as compared to the native neoplasms. MIB 1 was significantly lower in cases treated with NACT and survival outcome was significantly better in cases with low MIB 1. ER expression was associated with poor overall survival. No other marker displayed any significant difference in expression or correlation with survival between the two groups. Immunophenotype of SOC does not differ significantly in samples from cases treated with NACT, compared to upfront surgically treated cases. The proliferating capacity of the residual tumor cells is less, depicted by low mean MIB1 LI. MIB 1 and ER inversely correlate with survival

Cytopathology Using High Resolution Digital Holographic Microscopy

We summarize a study involving simultaneous imaging of cervical cells from Pap-smear samples using bright-field and quantitative phase microscopy. The optimization approach to phase reconstruction used in our study enables full diffraction limited performance from single-shot holograms and is thus suitable for reducing cost of a quantitative phase microscope system. Over 48000 cervical cells from patient samples obtained from three clinical sites have been imaged in this study. The clinical sites used different sample preparation methodologies and the subjects represented a range of age groups and geographical diversity. Visual examination of quantitative phase images of cervical cell nuclei show distinct morphological features that we believe have not appeared in the prior literature. A PCA based analysis of numerical parameters derived from the bright-field and quantitative phase images of the cervical cells shows good separation of superficial, intermediate and abnormal cells. The distribution of phase based parameters of normal cells is also shown to be highly overlapping among different patients from the same clinical site, patients across different clinical sites and for two age groups (below and above 30 years), thus suggesting robustness and possibility of standardization of quantitative phase as an imaging modality for cell classification in future clinical usage

Boomerang: Rebounding the consequences of reputation feedback on crowdsourcing platforms

Paid crowdsourcing platforms suffer from low-quality workand unfair rejections, but paradoxically, most workers and requesters have high reputation scores. These inflated scores, which make high-quality work and workers difficult to find,stem from social pressure to avoid giving negative feedback. We introduce Boomerang, a reputation system for crowdsourcing that elicits more accurate feedback by rebounding the consequences of feedback directly back onto the person who gave it. With Boomerang, requesters find that their highly rated workers gain earliest access to their future tasks, and workers find tasks from their highly-rated requesters at the top of their task feed. Field experiments verify that Boomerang causes both workers and requesters to provide feedback that is more closely aligned with their private opinions. Inspired by a game-theoretic notion of incentive-compatibility, Boomerang opens opportunities for interaction design to incentivize honest reporting over strategic dishonesty

Common variants in CLDN2 and MORC4 genes confer disease susceptibility in patients with chronic pancreatitis

A recent Genome-wide Association Study (GWAS) identified association with variants in X-linked CLDN2 and MORC4 and PRSS1-PRSS2 loci with Chronic Pancreatitis (CP) in North American patients of European ancestry. We selected 9 variants from the reported GWAS and replicated the association with CP in Indian patients by genotyping 1807 unrelated Indians of Indo-European ethnicity, including 519 patients with CP and 1288 controls. The etiology of CP was idiopathic in 83.62% and alcoholic in 16.38% of 519 patients. Our study confirmed a significant association of 2 variants in CLDN2 gene (rs4409525—OR 1.71, P = 1.38 x 10-09; rs12008279—OR 1.56, P = 1.53 x 10-04) and 2 variants in MORC4 gene (rs12688220—OR 1.72, P = 9.20 x 10-09; rs6622126—OR 1.75, P = 4.04x10-05) in Indian patients with CP. We also found significant association at PRSS1-PRSS2 locus (OR 0.60; P = 9.92 x 10-06) and SAMD12-TNFRSF11B (OR 0.49, 95% CI [0.31–0.78], P = 0.0027). A variant in the gene MORC4 (rs12688220) showed significant interaction with alcohol (OR for homozygous and heterozygous risk allele -14.62 and 1.51 respectively, P = 0.0068) suggesting gene-environment interaction. A combined analysis of the genes CLDN2 and MORC4 based on an effective risk allele score revealed a higher percentage of individuals homozygous for the risk allele in CP cases with 5.09 fold enhanced risk in individuals with 7 or more effective risk alleles compared with individuals with 3 or less risk alleles (P = 1.88 x 10-14). Genetic variants in CLDN2 and MORC4 genes were associated with CP in Indian patients

Global burden of 288 causes of death and life expectancy decomposition in 204 countries and territories and 811 subnational locations, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

BACKGROUND Regular, detailed reporting on population health by underlying cause of death is fundamental for public health decision making. Cause-specific estimates of mortality and the subsequent effects on life expectancy worldwide are valuable metrics to gauge progress in reducing mortality rates. These estimates are particularly important following large-scale mortality spikes, such as the COVID-19 pandemic. When systematically analysed, mortality rates and life expectancy allow comparisons of the consequences of causes of death globally and over time, providing a nuanced understanding of the effect of these causes on global populations. METHODS The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 cause-of-death analysis estimated mortality and years of life lost (YLLs) from 288 causes of death by age-sex-location-year in 204 countries and territories and 811 subnational locations for each year from 1990 until 2021. The analysis used 56 604 data sources, including data from vital registration and verbal autopsy as well as surveys, censuses, surveillance systems, and cancer registries, among others. As with previous GBD rounds, cause-specific death rates for most causes were estimated using the Cause of Death Ensemble model-a modelling tool developed for GBD to assess the out-of-sample predictive validity of different statistical models and covariate permutations and combine those results to produce cause-specific mortality estimates-with alternative strategies adapted to model causes with insufficient data, substantial changes in reporting over the study period, or unusual epidemiology. YLLs were computed as the product of the number of deaths for each cause-age-sex-location-year and the standard life expectancy at each age. As part of the modelling process, uncertainty intervals (UIs) were generated using the 2·5th and 97·5th percentiles from a 1000-draw distribution for each metric. We decomposed life expectancy by cause of death, location, and year to show cause-specific effects on life expectancy from 1990 to 2021. We also used the coefficient of variation and the fraction of population affected by 90% of deaths to highlight concentrations of mortality. Findings are reported in counts and age-standardised rates. Methodological improvements for cause-of-death estimates in GBD 2021 include the expansion of under-5-years age group to include four new age groups, enhanced methods to account for stochastic variation of sparse data, and the inclusion of COVID-19 and other pandemic-related mortality-which includes excess mortality associated with the pandemic, excluding COVID-19, lower respiratory infections, measles, malaria, and pertussis. For this analysis, 199 new country-years of vital registration cause-of-death data, 5 country-years of surveillance data, 21 country-years of verbal autopsy data, and 94 country-years of other data types were added to those used in previous GBD rounds. FINDINGS The leading causes of age-standardised deaths globally were the same in 2019 as they were in 1990; in descending order, these were, ischaemic heart disease, stroke, chronic obstructive pulmonary disease, and lower respiratory infections. In 2021, however, COVID-19 replaced stroke as the second-leading age-standardised cause of death, with 94·0 deaths (95% UI 89·2-100·0) per 100 000 population. The COVID-19 pandemic shifted the rankings of the leading five causes, lowering stroke to the third-leading and chronic obstructive pulmonary disease to the fourth-leading position. In 2021, the highest age-standardised death rates from COVID-19 occurred in sub-Saharan Africa (271·0 deaths [250·1-290·7] per 100 000 population) and Latin America and the Caribbean (195·4 deaths [182·1-211·4] per 100 000 population). The lowest age-standardised death rates from COVID-19 were in the high-income super-region (48·1 deaths [47·4-48·8] per 100 000 population) and southeast Asia, east Asia, and Oceania (23·2 deaths [16·3-37·2] per 100 000 population). Globally, life expectancy steadily improved between 1990 and 2019 for 18 of the 22 investigated causes. Decomposition of global and regional life expectancy showed the positive effect that reductions in deaths from enteric infections, lower respiratory infections, stroke, and neonatal deaths, among others have contributed to improved survival over the study period. However, a net reduction of 1·6 years occurred in global life expectancy between 2019 and 2021, primarily due to increased death rates from COVID-19 and other pandemic-related mortality. Life expectancy was highly variable between super-regions over the study period, with southeast Asia, east Asia, and Oceania gaining 8·3 years (6·7-9·9) overall, while having the smallest reduction in life expectancy due to COVID-19 (0·4 years). The largest reduction in life expectancy due to COVID-19 occurred in Latin America and the Caribbean (3·6 years). Additionally, 53 of the 288 causes of death were highly concentrated in locations with less than 50% of the global population as of 2021, and these causes of death became progressively more concentrated since 1990, when only 44 causes showed this pattern. The concentration phenomenon is discussed heuristically with respect to enteric and lower respiratory infections, malaria, HIV/AIDS, neonatal disorders, tuberculosis, and measles. INTERPRETATION Long-standing gains in life expectancy and reductions in many of the leading causes of death have been disrupted by the COVID-19 pandemic, the adverse effects of which were spread unevenly among populations. Despite the pandemic, there has been continued progress in combatting several notable causes of death, leading to improved global life expectancy over the study period. Each of the seven GBD super-regions showed an overall improvement from 1990 and 2021, obscuring the negative effect in the years of the pandemic. Additionally, our findings regarding regional variation in causes of death driving increases in life expectancy hold clear policy utility. Analyses of shifting mortality trends reveal that several causes, once widespread globally, are now increasingly concentrated geographically. These changes in mortality concentration, alongside further investigation of changing risks, interventions, and relevant policy, present an important opportunity to deepen our understanding of mortality-reduction strategies. Examining patterns in mortality concentration might reveal areas where successful public health interventions have been implemented. Translating these successes to locations where certain causes of death remain entrenched can inform policies that work to improve life expectancy for people everywhere. FUNDING Bill & Melinda Gates Foundation

Anti-tumor studies with extracts of <i>Calotropis procera</i> (Ait.) R.Br. root employing Hep2 cells and their possible mechanism of action

343-348Anti-tumor potential of root extracts of Calotropis procera : methanolic extract (CM), hexane extract (CH), aqueous extract (CW) and ethylacetate extract (CE) and its possible mechanism against Hep2 cancer cells has been investigated. Cellular proliferation activities were assayed by tetrazolium bromide (MTT) colorimetry. Morphological changes of cancer cells were observed under inverted microscope and cell cycle parameters were determined by flow cytometry following propidium iodide staining. Treatment with the extracts at various doses of 1, 5, 10 and 25 µg/ml revealed that CM, CH and CE possessed cytotoxicity, whereas CW did not have cytotoxic effect. CE (10 µg/ml) showed strongest cytotoxic effect (96.3%) on Hep2 at 48 hr following treatment, whereas CM and CH showed cytotoxicity of 72.7 and 60.5%, respectively. Extract-treated cells exhibited typical morphological changes of apoptosis. Results of flow cytometric analysis clearly demonstrated that root extracts initiated apoptosis of Hep2 cells through cell cycle arrest at S phase, thus preventing cells from entering G2/M phase. Results of the study indicate that the root extracts of C. procera inhibit the proliferation of Hep2 cells via apoptotic and cell cycle disruption based mechanisms. </span